Second generation knockout sickle mice: the effect of HbF
Second generation knockout sickle mice: the effect of HbF
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DOI：
10.1182/blood.v97.2.410
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发表时间：
2001-01-15
期刊：
影响因子：
20.3
通讯作者：
Nagel, RL
中科院分区：
文献类型：
--
作者：
Fabry, ME;Suzuka, SM;Nagel, RL
专门表达人球蛋白的镰状转基因小鼠对于研究病理生理学和测试基因治疗策略是理想的，但是它们必须具有显著的病理学并且显示抗镰状血红蛋白改善的证据。使用它们先前描述的镰状构建体产生专门表达具有3个HbF水平的人镰状血红蛋白的小鼠（共整合的人miniLCR α 2和miniLCR β（S）[PNAS 89：12150，1992]）、小鼠α-和β-球蛋白-敲除以及3种不同的人γ-转基因的研究中，发现在所有3种HbF表达水平下，这些小鼠具有平衡的链合成、几乎正常的平均红细胞血红蛋白以及在某些情况下的F细胞。具有最少成人HbF表达的小鼠是最严重的。HbF从小于3%逐渐增加至20%至40%与红细胞压积的逐渐增加相关（22%-34%-40%）和网织红细胞计数进行性降低（从60%至30%至13%），尿浓缩能力在高HbF下正常化，并且通过组织病理学和器官重量缺陷的组织损伤通过HbF增加而改善，将产生中等水平HbF的γ-转基因引入由Paszty及其同事描述的基因敲除镰状小鼠中，所述基因敲除镰状小鼠表达miniLCR α 1（G）γ（A）γ δ β（S）转基因并且具有胎儿但非成人HbF表达，发现改善低血细胞比容和使尿浓缩缺陷正常化所需的HbF水平对于miniLCR α 2 β（S）是不同的。和miniLCR α 1（G）γ（A）γ δ β（S）小鼠。我们的结论是，具有miniLCR α 2 β（S）转基因和出生后表达HbF的敲除小鼠具有足够忠实的镰状病变，可以作为测试抗镰状干预的平台。(C)2001年，美国血液学会。
Sickle transgenic mice expressing exclusively human globins are desirable for studying pathophysiology and testing gene therapy strategies, but they must have significant pathology and show evidence of amelioration by antisickling hemoglobins, Mice were generated that expressed exclusively human sickle hemoglobin with 3 levels of HbF using their previously described sickle constructs (cointegrated human miniLCR alpha2 and miniLCR beta (S) [PNAS 89:12150, 1992]), mouse alpha- and beta -globin-knockouts, and 3 different human gamma -transgenes, it was found that, at all 3 levels of HbF expression, these mice have balanced chain synthesis, nearly normal mean corpuscular hemoglobin, and, in some cases, F cells, Mice with the least adult HbF expression were the most severe. Progressive increase in HbF from less than 3% to 20% to 40% correlated with progressive increase in hematocrit (22% to 34% to 40%) and progressive decrease in reticulocyte count (from 60% to 30% to 13%), Urine concentrating ability was normalized at high HbF, and tissue damage defected by histopathology and organ weight were ameliorated by increased HbF, The gamma -transgene that produces intermediate levels of HbF was introduced into knockout sickle mice described by Paszty and coworkers that express the miniLCR alpha1(G)gamma (A)gamma delta beta (S) transgene and have fetal but not adult expression of HbF, It was found that the level of HbF required to ameliorate low hematocrit and normalize urine concentrating defect was different for the miniLCR alpha2 beta (S) and miniLCR alpha1(G)gamma (A)gamma delta beta (S) mice. We conclude that knockout mice with the miniLCR alpha2 beta (S) transgene and postnatal expression of HbF have sufficiently faithful sickle pathology to serve as a platform for testing antisickling interventions. (C) 2001 by The American Society of Hematology.